Intraoperative radiotherapy: An alternative to whole‐breast external beam radiotherapy in the management of highly selective breast cancer: A SEER database analysis

Abstract Objective This study aimed to verify if intraoperative radiotherapy (IORT) can achieve the same survival outcome as whole‐breast external beam radiotherapy (EBRT) in early breast cancer after breast‐conserving surgery (BCS), and to explore the suitable candidates that can safely receive IORT after BCS. Methods Eligible post‐BCS patients who received IORT or EBRT were included in the Surveillance, Epidemiology and End Results (SEER) database from 2010 to 2018. Risk factors that affected 5‐year overall survival (OS) or breast cancer specific survival (BCSS) were identified by Cox proportional hazards regression analysis. Clinical characteristics, OS, and BCSS were comparatively analyzed between the two treatment modalities. Results The survival analysis after propensity score matching confirmed that patients who received IORT (n = 2200) had a better 5‐year OS than those who received EBRT (n = 2200) (p = 0.015). However, the two groups did not differ significantly in 5‐year BCSS (p = 0.381). This feature persisted even after multivariate analyses that took into account numerous clinical characteristics. Although there was no significant difference in BCSS between different subgroups of patients treated with IORT or EBRT, patients over 55 years of age, with T1, N0, non‐triple negative breast cancers, hormone receptor‐positive, and histologic grade II showed a better OS after receiving IORT. Conclusion In low‐risk, early‐stage breast cancer, IORT was not inferior to EBRT considering 5‐year BCSS and OS. Considering the equivalent clinical outcome but less radiotoxicity, IORT might be a reasonable alternative to EBRT in highly selective patients undergoing BCS.


| INTRODUCTION
Whole-breast external beam radiotherapy (EBRT) has been the international standard radiotherapy regimen after breast-conserving surgery (BCS) for early-stage breast cancer, 1,2 patients who received whole-breast irradiation had a 15.7% lower 10-year risk of recurrence and a 3.8% lower 15-year risk of breast cancer death compared with patients who did not receive wholebreast irradiation. 3The standard regimen for EBRT is 45-50 Gy in 25-28 fractions for 5-7 weeks of radiotherapy to the whole breast.To shorten the course of radiotherapy, some studies have used a hypofractionated regimen, which is 39-42.9Gy in a single fractional dose of 2.6-3.3Gy divided into 13 fractions to be radiographed within 5 weeks. 4However, EBRT is associated with postoperative complications, including breast deformity morbidities, superficial ulcers of the skin, and local sensory dysfunction. 5,6In addition to the fact that hypofractionated regimens may be more likely to result in the adverse effects described above than conventional fractionation regimens, certain patients with other comorbidities or who are more frail may be less able to tolerate the effects of hypofractionated regimens.At the same time, postoperative radiotherapy-related factors such as the long treatment duration, cost of treatment, and far distance to treatment centers also prevent some patients from receiving postoperative radiotherapy. 5,7,8hat is more, in the era of effective multimodal therapy, full conventional EBRT irradiating the whole breast may now be unnecessary in all patients, especially those with a very low risk of recurrence.Consequently, new concepts of more personalized risk-adapted approaches have been tested and applied in clinical settings.
As a de-escalation postoperative radiotherapy, intraoperative radiotherapy (IORT) 9 is a treatment strategy in which postoperative EBRT is substituted by a single shot of radiation to the tumor bed at an 18-24 Gy dose given during the surgical procedure. 10Results of randomized controlled clinical studies of IORT in early breast cancer suggest satisfactory outcomes in terms of overall survival and late adverse effects.2][13][14][15][16] These results made IORT seem to be a reasonable alternative to whole-breast EBRT in specific patients.In the meantime, IORT as a one-time therapy reduces treatment duration and noncompliance to postoperative radiation.However, electron intraoperative radiotherapy (ELIOT) trial 13 reported a significantly higher risk of ipsilateral breast tumor recurrence in patients in the IORT group (4.4%) compared to patients in the EBRT group (0.4%), which means that we have to balance the tumor recurrence risk and convenience of IORT and select proper candidates for IORT.Perhaps only rigorously screened patients who are hormone receptor-positive and human epidermal growth factor receptor 2 (HER2) negative, with small tumors and no axillary lymph node metastases, should be treated with IORT as an alternative to EBRT.
Considering EBRT may be unnecessary in all patients.Stricter selection of candidates with early breast cancer for IORT is mandatory to avoid unnecessary EBRT in these patients while ensuring their clinical efficacy.In this study, we selected low-risk (T1-T2, N0-N1, M0) patients who underwent BCS, from the Surveillance, Epidemiology, and End Results (SEER) database, which is a large, nationwide population-based registry.The survival outcomes of patients in the IORT group were compared to the patients in the EBRT group to find out whether the patients we selected were the proper candidates for IORT.We also evaluated clinicopathological factors significantly associated with clinical outcomes in the IORT and EBRT groups.

| Study variables and outcomes
Demographic and disease characteristics identified and collected in the SEER database for this study include age, ethnicity, T stage, N stage, chemotherapy, systemic/ surgery sequence, estrogen receptor (ER) status, progesterone (PR) status, HER2 status, marital status, patient's hospital of regions, histological grade, histological type.The primary endpoint was OS, and the second endpoint was BCSS, with OS defined as the duration from the day of diagnosis to death.BCSS is defined as the time from initial diagnosis to death from any cause related to cancer.Cohort patients were followed until patient death and ended in 2018.

| Statistical analysis
Categorized data are presented as a number (N) or a percentage (%).All statistical analyses were performed using R language (version 4.2.0).To eliminate significant differences in baseline covariates and inherent selection bias, propensity score matching (PSM) analyses were performed between the IORT and EBRT groups.The PSM is a tool to narrow selection bias and achieve a balance of variables across treatment groups in non-randomized studies.IORT and EBRT were matched in a 1:1 ratio using a propensity model.Clinicopathological features that have a significant impact on clinical outcomes: age, T stage, N stage, chemotherapy, systemic/surgery sequence, breast cancer type (triple negative or non-triple negative), ER status, PR status, HER2 status, histological grade, and histological type.The Kaplan-Meier survival curve was used for survival analysis between the IORT group and the EBRT group.An univariate Cox regression survival test was used for hypothesis testing to determine the risk prognostic factors affecting OS and BCSS.Multivariate Cox regression was used to analyze the independent prognostic risk factors.Corresponding hazard ratios (HR) and 95% confidence intervals (CI) were reported.
There were no lost patients in this study because of the exclusion of patients with incomplete information.

| Screening process
From 2010 to 2018, we collected a total of 293,691 female breast cancer patients undergoing BCS in the SEER database, and excluded 153,253 patients after exclusion screening, with a total of 140,438 eligible patients (Figure 1).According to the proportion of the IORT group and EBRT group per year, we made a proportion distribution map from 2010 to 2018 (Figure 2), which could be intuitively found that the proportion of patients in the IORT group increased year by year from 2010 to 2014 (0.25%-1.90%).The proportion of patients with IORT and EBRT remained relatively stable (1.90%-1.98%)from 2014 to 2018.A total of 4400 patients were enrolled in the study after a 1:1 PSM between 2200 patients receiving IORT and the EBRT group.

| Baseline characteristics
Among the 4400 patients who met the analysis criteria, the important characteristics (age, T stage, N stage, chemotherapy, systemic/surgery sequence, breast cancer type (triple negative or non-triple negative), ER status, PR status, HER2 status, histological grade, and histological type) of the two groups were well matched (Table 1).Eligible patients were early-stage: 3639 (82.70%) were older than 55 years, 3835 (87.16%) were T1, 4209 (95.66%) were N0, 3963 (90.07%) did not receive chemotherapy The pathologic features of the majority of patients showed a lowrisk profile: 4270 (97.05%) were non-triple negative breast cancer, 4217 (95.84%) were ER-positive, 3879 (88.16%) were PR-positive, and 4189 (95.20%) were HER2-negative.Those with histologic classification of grade I and II (n = 3856, 87.64%) accounted for the largest number of patients.These clinical characteristics were not significantly different in the IORT and EBRT groups, which meant that they were comparable between the two groups.
In multivariate COX regression analysis (Table 2), age >55 (p < 0.001), T2 (p < 0.001), and marital status (separated/divorced/widowed/unknown, p < 0.001) were the risk prognostic factors of OS, while PR positive (p = 0.027) and histological type (mixed, p = 0.004) seem to be associated with a better prognosis.Slightly different from this was that T2 (p < 0.001), N1 (p = 0.049), PR negative (p = 0.012), histological grade II (p = 0.015) and histological grade III (p = 0.011) were the risk prognostic factors of BCSS.Overall, elevated TNM stage and increased type of pathology portend a poor prognosis.It was worth noting that there was a significant difference in OS between IORT and EBRT, but not in BCSS (OS: p = 0.020; BCSS: p = 0.190).

| DISCUSSION
In recent years, clinicians have been in the pursuit of the least treatment to achieve the best outcome.8][19] The formation of an ideal adjuvant radiotherapy strategy for patients should be based on risk stratification of patients.IORT is a relatively convenient form of radiotherapy, and studies have shown that IORT as an adjuvant radiotherapy is not inferior to EBRT in the overall survival of early and low-risk breast cancer  patients. 13,141][22][23][24] This study aimed to evaluate the application of IORT in the real world: 1.The efficacy of IORT as adjuvant radiotherapy compared with EBRT in the real world for early-stage low-risk post-BCS patients; 2. To explore the most suitable candidates for IORT as adjuvant therapy.At a median follow-up of 6.25 years (0-8.92years) in the SEER database, the 5-year survival rate was 97.0% with BCS-combined IORT patients versus 95.5% with BCS-combined EBRT patients after 1:1 PSM (p = 0.015), it seems that patients in IORT group had better overall survival.However, BCSS was 99.4% with BCS-combined IORT patients versus 98.9% with BCS-combined EBRT in 5 years (p = 0.381).It indicated that BCS-combined with IORT was not inferior to that of EBRT in terms of risk of death related to breast cancer in our selected patients, which is consistent with the results of two previous large studies, ELIOT and TARGIT-A. 13,14e included the IORT group with the largest number of patients (n = 2200) in our study.It was not difficult to find that the number of patients who received IORT as adjuvant therapy had increased from 2010 to 2014 (0.25%-1.90%) but remained basically stable from 2014 to 2018 (1.90%-1.98%).A global survey of IORT applications found that IORT had been used in 35 countries and at least 44,752 breast cancer patients had received IORT. 25In an Italian survey of clinical practice questions, 34% used IORT as the preferred method of partial breast irradiation.Strict criteria had been established for the practice of IORT in Germany, such as age >50 years, T1N0M0, and IDC.It is estimated that about 10%-15% of patients undergoing BCS would be eligible for IORT as solo radiotherapy. 26It shows that IORT has been raised more attention and applied to some extent in the real world.
IORT has certain advantages over EBRT in the localization of target lesions.It must be mentioned the concept of "geographical miss", which was first proposed by Felix Sedlmayer. 27It is referring to: even if titanium clips are used to locate the tumor bed during the operation, we may miss the real tumor bed due to the traction and displacement of the tissue or the high fluidity of the breast due to the rich fat content after the operation, which may be one of the reasons for the local recurrence of BCS after radiotherapy.IORT is performed immediately during surgery, which can directly irradiate the tissues around the tumor, avoid the loss of tumor bed, and improve the targeting and accuracy of radiotherapy.9][30][31] In addition, IORT only takes a very short radiation time, generally less than 30 min, because it is a single dose of radiation performed during the surgery.Finally, compared with EBRT, the treatment cost of IORT has been greatly reduced.It reported that IORT can save 1800 pounds per patient only in treatment, not to mention the transportation costs for treatment.Similarly, in terms of British finance, IORT can even save 13 million pounds per year. 32According to our patients, the savings can be as much as $7000.
By analyzing 11 randomized trials, Lis Victoria Ravani et al. 33 found that patients treated with IORT had a higher rate of ipsilateral breast tumor recurrence (IBTR) than those treated with partial breast irradiation (PBI) and standard or moderately hypofractionated EBRT, compared with no difference in OS or diseasefree survival (DFS).Marina Guenzi et al. 34 also found a higher local recurrence of IORT (3.4%) than hypofractionated EBRT (0.42%, 39 Gy/13 fractions, plus an individualized concomitant boost to the tumor bed up to 42-43 Gy) through 6 years of long-term follow-up, a finding that may be relevant to certain subgroups of patients who, based on the biology of their breast cancer, may be less amenable to IORT.Interestingly, there was no significant difference in health-related quality of life between the regimens of IORT ( 1 Note: Categorized data are presented as a number (N) or a percentage (%).p ≤ 0.05 indicates statistical significance.
Abbreviations: EBRT, external beam radiotherapy; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma; IORT, intraoperative radiotherapy; PR, progesterone receptor; SES, salary economic states (Based on per capita GDP data from the US Bureau of Economic Analysis in 2020, we divided the state of the patient's medical institution into high SES (≥$80000) and low SES (<$80000)).
T A B L E 1 (Continued) SUN et al.
hypofractionated EBRT + boost (21-26 × 2.67 Gy), and simultaneous EBRT + boost (28 × 2.3 Gy). 35revious studies have found that as many as 15%-30% of early breast cancer patients who undergo BCS do not receive postoperative radiotherapy. 5The main reasons include that some patients live far from the radiotherapy center and is not convenient to receive radiotherapy, or some patients have other comorbidities, or due to financial pressure, especially in the elderly population.Even some patients meet the surgical criteria for BCS who choose mastectomy just to avoid radiotherapy. 36Therefore, IORT perhaps offers a relatively good option for these pathologically low-risk patients if they have difficulty receiving conventional radiotherapy.This is also why more and more patients prefer IORT as a post-BCS adjutant therapy.In the Italian study, 26 many patients preferred to choose intraoperative radiotherapy at the risk of recurrence.][39] With any treatment, we have to balance it with the adverse effects it brings.EBRT as a standard adjuvant treatment after BCS also brings many ineligible side effects and may achieve limited benefits in certain very low-recurrence risk patients.Grit Welzel et al reported the IORT group had less postoperative pain in the whole body, arm, and breast, and better functional activity (p < 0.01) compared to EBRT. 11According to TARGIT-A, 40 grade III-IV radiation-related complications such as dermatitis, telangiectasis, and pain at the radiation site were significantly lower in the IORT group than in the EBRT group 20 (median follow-up: 4 years, 0.5% vs. 2.1%, p = 0.002).Chronic toxicities such as skin fibrosis and telangiectasis were also lower in the IORT group than that in the EBRT group (5.9% vs. 18.1%, 0 vs. 17.7%). 12IORT also can achieve a better cosmetic effect because of little radiation damage to the local skin that causes an inflammatory response and fibrosis in the breast skin.Breast esthetics is a very important outcome of patients' concerns after BCS.Mohammed et al 41 evaluated that IORT had better cosmetic results (such as breast symmetry, scar, and color change) than EBRT at either 1 or 2 years after BCS (1 year: OR 2.07, 95% CI 1.12-3.85,p = 0.021; 2-year: OR 2.11, 95% CI 1.0-4.45,p = 0.05).Therefore, IORT has great advantages in terms of adverse effects.
As for 5-year OS, patients who received targeted IORT represented better outcomes than those who received whole-breast EBRT, however, the main difference came from non-BCSS related deaths.Breast cancer mortality was much the same between groups reconfirming the non-inferiority of targeted IORT for early breast cancer better in our study.Our results are consistent with that of ELIOT and TARGIT-A, which may be related to the relatively lower recurrence risk of patients in the IORT group in our study (T1: 87.18%, N0: 95.64%, non-triple-negative breast cancer: 97.05%).TARGIT-A adopts a risk-adapted design, 14 for patients will be given additional EBRT after IORT if the final pathology report shows unpredicted prespecified adverse features, which indicates that IORT should be individualized and it is necessary to carefully select patients with low-risk of recurrence.ELIOT 13 showed that although there was no significant difference in OS between IORT and EBRT (median follow-up 13.1 years, p = 0.85), the local recurrence rate of IORT alone was higher than that of EBRT (median follow-up 12.4 years, IORT 11% vs. EBRT 2%, p < 0.0001).This may be related to the  relatively high lymph node involvement in ELIOT patients (T2: 13%, N positive: 26%, triple-negative breast cancer: 7%), and it may not be sufficient to give local tumor bed radiotherapy alone in these node-metastasis patients.For very low-risk breast cancer (T<1 cm, histologic grade I, luminal A, and Ki-67<14%) in the ELIOT trial, IORT was associated with a similar 10-year local recurrence rate compared with EBRT (1.3% vs. 1.5%, p = 0.45), suggesting that IORT can be safely performed in highly selected low-risk patients.In addition to this, it has also been shown that in women aged 65 years and older with low-risk, lymph node-negative, hormone receptor-positive, early-stage primary breast cancer, the absence of radiotherapy is associated with an increased incidence of local recurrence, but has no detrimental effect on distant recurrence as a first event or on overall survival. 42In our further subgroup analysis, IORT was more suitable for patients >55 years old, with T1, N0, ER positive, PR positive, non-triple negative breast cancer, and grade I-II histology, also consistent with the patients enrolled in the TARGIT-A study.Therefore, we believe that EBRT after BCS is still a routine treatment for breast cancer patients, but IORT is also a viable alternative to EBRT for certain patients with low-risk breast cancer.This study has the following limitations.First, it could not address detailed information on local recurrence and distant metastasis.Local recurrence is an important factor in evaluating local control of radiotherapy.Second, the SEER database can't provide specific information on radiation dose, endocrine therapy, anti-HER2 therapy, or chemotherapeutic, which may cause potential bias in our study.

| CONCLUSION
The results showed that patients who received IORT had better 5-year OS than those who received EBRT, but there was no significant difference between the two groups in terms of 5-year BCSS.Those older than 55 years, T1, N0, non-triple negative breast cancer, ER positive, PR positive, and grade II histology are more likely to benefit from IORT treatment.Therefore, IORT may be a reasonable alternative to EBRT for highly selective breast-conserving patients with early-stage breast cancer.

F I G U R E 1
Flow chart of patient selection.IORT, intraoperative radiotherapy; EBRT, external beam radiotherapy; PSM, propensity score matching.F I G U R E 2 Percent of patients who received EBRT or IORT between 2010 and 2018.IORT, intraoperative radiotherapy; EBRT, external beam radiotherapy.The figure illustrates the ratio of IORT to the total number of radiotherapy patients in the year.| 5 of 12 SUN et al.

F I G U R E 3
Kaplan-Meier overall survival curve of patients who received IORT or EBRT after PSM (A), and breast cancer specific survival curve after PSM (B).IORT, intraoperative radiotherapy; EBRT, external beam radiotherapy; PSM, propensity score matching; OS, overall survival; BCSS, breast cancer specific survival; Hazard ratios (HR) were used to analyze 5-year survival.p ≤ 0.05 indicates statistical significance.

2.1 | Design, data source, and study cohort
Baseline characteristics after propensity score matching.
T A B L E 1 × 23.3 Gy), PBI (10 × 3.85 Gy), hypofractionated EBRT (16 × 2.67 Gy), Multivariate Cox regression survival analysis was performed to identify independent prognostic factors for OS and BCSS in patients with BCS who underwent EBRT or IORT.